Insulin-dependent or Type 1 diabetes is a major public health problem resulting in blindness, kidney failure, nerve and vascular damage and life-threatening acute metabolic problems. Currently, successful treatment is directed at the organs involved in these complications and insulin replacement. Understanding the origin of insulin-dependent diabetes could result in specific treatment aimed at correcting endogenous insulin deficiency. Immune abnormalities have been associated with insulin-dependent diabetes, and thus several in vitro quantitative and functional immunologic techniques have been developed. The functional in vitro immunologic assays include: a) immune regulatory studies using mixed lymphocyte-islet cell cultures, allogeneic and autologous mixed lymphocyte reactivity, and the production of and responsiveness to interleukin-2, b) immune islet killing studies using patient effector cells and/or antibody and islet target cells, and c) complement activation studies using islet cell induced C3 and Factor B consumption induced by serum from diabetic subjects and measurement of circulating levels of C3a, C4a, C5a, C5 activation antigen, and Factor B in patient plasma. To more directly characterize the immunological abnormalities, both cross-sectional and longitudinal designs will be used. To evaluate the natural history of immune dysfunction, insulin-dependent diabetic patients will be evaluated during disease onset, remission and thereafter using the longitudinal design. The immunologic in vitro studies will then be correlated with endogenous islet B cell function by measuring basal and stimulated circulating C-peptide levels, so as to relate the immune abnormalities to islet B cell function. Cross-sectional studies will evaluate disease specificity (Type 2 diabetic controls), disease activity (new onset, remission and chronic Type 1 studies) and genetics (HLA matched control groups). These studies may provide initial data to permit a reassessment of the current treatment of Type 1 diabetes. The health care impact of determining a treatable cause of Type 1 diabetes is of major social, medical and economic significance.